Colorectal cancer (CRC) represents a serious public health problem that affects African Americans (AA) disproportionately. Both incidence rates and morbidity and mortality is higher in AAs than in other Americans. Family history, that is, genetic risk, remains one of the most important factors in recommendations for screening. Recent genome-wide association studies have identified 10 independent regions harboring genetic risk factors in CRC in populations of European ancestry. Using single-nucleotide polymorphisms (SNPs) from these studies, we have obtained evidence of association in four of these regions in AA CRC. Our goal is to identify the functional genetic risk factors, quantify their effects, and determine their functions. To pursue this goal, we propose four Aims. (1) We will validate previously identified candidate CRC-associated regions in AA CRC cases and controls. We will use Sequenom genotyping and tag SNPs from these regions to identify SNPs associated with CRC in AAs. We will use 100 ancestry informative markers to perform a structured logistic regression analysis that takes into account possible population stratification based on ancestry. Because AAs are more diverse than European Americans, these studies will very likely lead to better localization of the genetic risk factors. (2) We will use Next Generation Sequencing (NGS) technology to conduct a resequencing analysis of each candidate genetic region in 96 (48 CRC and 48 controls) persons with CRC. The region that we resequence will be guided by the genes and linkage disequilibrium observed in each CRC-associated region. (3) We will better quantify the effects of the genetic risk factors in each region. We will perform a bioinformatics analysis to identify putative functional variants. These functional candidates along with our novel genetic variants in CRC-associated regions will be genotyped in up to 2000 AA cases and 2000 AA control. We will perform structured logistic regression analysis to obtain the strongest genotype relative risks in each CRC-associated regions. (4) The foregoing analyses will provide a short-list of candidate genetic risk factors for each CRC-associated region. We will begin to characterize the molecular basis of CRC risk for each region by functional assays designed based on the putative mechanism caused by the genetic variants (regulatory or enzymatic). Molecular assays (for example, luciferase reporter assays) will be designed to determine the functional impact of candidate genetic risk factors.